The environment of the CNS is inhibitory to axonal regeneration after injury, in large part due to inhibitors present in myelin, such as myelin associated glycoprotein (MAG). We have shown that elevating cAMP can overcome myelin inhibitors of regeneration both in vitrb and in vivo. This cAMP effect is transcription- dependent; suggesting newly synthesized proteins are needed to overcome inhibition. Our lab has identified several genes that are up-regulated in response to cAMP, one of them is Metallothionein I (MT-I). We have preliminary data that MT-I/II can overcome MAG and myelin mediated inhibition in vitro, using several different primary neuronal cultures. More importantly, MT-I/II exerts its effect by simply being added to the neurons in the presence of the inhibitors. This suggests that MT-I/II may be a novel putative therapeutic agent for intervention to encourage regeneration in vivo. We are now poised to first characterizethe effects of MT-I/II in vitro and pursue a potential mechanism, which we suspect that MT-I/IJ is blocking the signaling pathway of MAG binding to the NgR-Lingo-p75 receptor complex that mediates this inhibition. We also plan to see if MT-I/II can promote axonal regeneration in an in vivo spinal cord injury model.